4ci5 - Revision history

OCA at 12:10, 20 December 2023

OCA — Wed, 20 Dec 2023 12:10:34 GMT

←Older revision		Revision as of 12:10, 20 December 2023
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4ci5]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CI5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CI5 FirstGlance]. <br>		<table><tr><td colspan='2'>[[4ci5]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CI5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CI5 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=Y1N:2-METHYL-2-[4-[2-[4-[(E)-PHENYLDIAZENYL]PHENOXY]ETHYL]PHENOXY]PROPANOIC+ACID'>Y1N</scene></td></tr>	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 1.77Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=Y1N:2-METHYL-2-[4-[2-[4-[(E)-PHENYLDIAZENYL]PHENOXY]ETHYL]PHENOXY]PROPANOIC+ACID'>Y1N</scene></td></tr>
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ci5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ci5 OCA], [https://pdbe.org/4ci5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ci5 RCSB], [https://www.ebi.ac.uk/pdbsum/4ci5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ci5 ProSAT]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ci5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ci5 OCA], [https://pdbe.org/4ci5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ci5 RCSB], [https://www.ebi.ac.uk/pdbsum/4ci5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ci5 ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[[https://www.uniprot.org/uniprot/PPARG_HUMAN PPARG_HUMAN]] Note=Defects in PPARG can lead to type 2 insulin-resistant diabetes and hyptertension. PPARG mutations may be associated with colon cancer. Defects in PPARG may be associated with susceptibility to obesity (OBESITY) [MIM:[https://omim.org/entry/601665 601665]]. It is a condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat.<ref>PMID:9753710</ref> Defects in PPARG are the cause of familial partial lipodystrophy type 3 (FPLD3) [MIM:[https://omim.org/entry/604367 604367]]. Familial partial lipodystrophies (FPLD) are a heterogeneous group of genetic disorders characterized by marked loss of subcutaneous (sc) fat from the extremities. Affected individuals show an increased preponderance of insulin resistance, diabetes mellitus and dyslipidemia.<ref>PMID:12453919</ref> <ref>PMID:11788685</ref> Genetic variations in PPARG can be associated with susceptibility to glioma type 1 (GLM1) [MIM:[https://omim.org/entry/137800 137800]]. Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas. Note=Polymorphic PPARG alleles have been found to be significantly over-represented among a cohort of American patients with sporadic glioblastoma multiforme suggesting a possible contribution to disease susceptibility.	+	[https://www.uniprot.org/uniprot/PPARG_HUMAN PPARG_HUMAN] Note=Defects in PPARG can lead to type 2 insulin-resistant diabetes and hyptertension. PPARG mutations may be associated with colon cancer. Defects in PPARG may be associated with susceptibility to obesity (OBESITY) [MIM:[https://omim.org/entry/601665 601665]. It is a condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat.<ref>PMID:9753710</ref> Defects in PPARG are the cause of familial partial lipodystrophy type 3 (FPLD3) [MIM:[https://omim.org/entry/604367 604367]. Familial partial lipodystrophies (FPLD) are a heterogeneous group of genetic disorders characterized by marked loss of subcutaneous (sc) fat from the extremities. Affected individuals show an increased preponderance of insulin resistance, diabetes mellitus and dyslipidemia.<ref>PMID:12453919</ref> <ref>PMID:11788685</ref> Genetic variations in PPARG can be associated with susceptibility to glioma type 1 (GLM1) [MIM:[https://omim.org/entry/137800 137800]. Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas. Note=Polymorphic PPARG alleles have been found to be significantly over-represented among a cohort of American patients with sporadic glioblastoma multiforme suggesting a possible contribution to disease susceptibility.
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/PPARG_HUMAN PPARG_HUMAN]] Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the receptor binds to a promoter element in the gene for acyl-CoA oxidase and activates its transcription. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses.<ref>PMID:9065481</ref> <ref>PMID:16150867</ref> <ref>PMID:20829347</ref>	+	[https://www.uniprot.org/uniprot/PPARG_HUMAN PPARG_HUMAN] Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the receptor binds to a promoter element in the gene for acyl-CoA oxidase and activates its transcription. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses.<ref>PMID:9065481</ref> <ref>PMID:16150867</ref> <ref>PMID:20829347</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-dependent transcription factors that control various functions in human organism, including the control of glucose and lipid metabolism. PPARgamma is a target of TZD agonists, clinically used to improve insulin sensitivity whereas fibrates, PPARalpha ligands, lower serum triglyceride levels. We report here the structural studies of GL479, a synthetic dual PPARalpha/gamma agonist, designed by a combination of clofibric acid skeleton and a phenyldiazenyl moiety, as bioisosteric replacement of stilbene group, in complex with both PPARalpha and PPARgamma receptors. GL479 was previously reported as a partial agonist of PPARgamma and a full agonist of PPARalpha with high affinity for both PPARs. Our structural studies reveal different binding modes of GL479 to PPARalpha and PPARgamma, which may explain the distinct activation behaviors observed for each receptor. In both cases the ligand interacts with a Tyr located at helix 12 (H12), resulting in the receptor active conformation. In the complex with PPARalpha, GL479 occupies the same region of the ligand-binding pocket (LBP) observed for other full agonists, whereas GL479 bound to PPARgamma displays a new binding mode. Our results indicate a novel region of PPARs LBP that may be explored for the design of partial agonists as well dual PPARalpha/gamma agonists that combine, simultaneously, the therapeutic effects of the treatment of insulin resistance and dyslipidemia.
		+
		+	Different binding and recognition modes of GL479, a dual agonist of Peroxisome Proliferator-Activated Receptor alpha/gamma.,Dos Santos JC, Bernardes A, Giampietro L, Ammazzalorso A, De Filippis B, Amoroso R, Polikarpov I J Struct Biol. 2015 Jul 14. pii: S1047-8477(15)30031-9. doi:, 10.1016/j.jsb.2015.07.006. PMID:26185032<ref>PMID:26185032</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 4ci5" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==

OCA at 17:47, 7 September 2022

OCA — Wed, 07 Sep 2022 17:47:05 GMT

←Older revision		Revision as of 17:47, 7 September 2022
Line 3:		Line 3:
	<StructureSection load='4ci5' size='340' side='right'caption='[[4ci5]], [[Resolution\|resolution]] 1.77Å' scene=''>		<StructureSection load='4ci5' size='340' side='right'caption='[[4ci5]], [[Resolution\|resolution]] 1.77Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4ci5]] is a 2 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CI5 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=4CI5 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4ci5]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CI5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CI5 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=Y1N:2-METHYL-2-[4-[2-[4-[(E)-PHENYLDIAZENYL]PHENOXY]ETHYL]PHENOXY]PROPANOIC+ACID'>Y1N</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=Y1N:2-METHYL-2-[4-[2-[4-[(E)-PHENYLDIAZENYL]PHENOXY]ETHYL]PHENOXY]PROPANOIC+ACID'>Y1N</scene></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4ci4\|4ci4]]</td></tr>~~	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ci5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ci5 OCA], [https://pdbe.org/4ci5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ci5 RCSB], [https://www.ebi.ac.uk/pdbsum/4ci5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ci5 ProSAT]</span></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://proteopedia.org/fgij/fg.htm?mol=4ci5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ci5 OCA], [~~http~~://pdbe.org/4ci5 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4ci5 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4ci5 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4ci5 ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== Disease ==
-	[[~~http~~://www.uniprot.org/uniprot/PPARG_HUMAN PPARG_HUMAN]] Note=Defects in PPARG can lead to type 2 insulin-resistant diabetes and hyptertension. PPARG mutations may be associated with colon cancer. Defects in PPARG may be associated with susceptibility to obesity (OBESITY) [MIM:[~~http~~://omim.org/entry/601665 601665]]. It is a condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat.<ref>PMID:9753710</ref> Defects in PPARG are the cause of familial partial lipodystrophy type 3 (FPLD3) [MIM:[~~http~~://omim.org/entry/604367 604367]]. Familial partial lipodystrophies (FPLD) are a heterogeneous group of genetic disorders characterized by marked loss of subcutaneous (sc) fat from the extremities. Affected individuals show an increased preponderance of insulin resistance, diabetes mellitus and dyslipidemia.<ref>PMID:12453919</ref> <ref>PMID:11788685</ref> Genetic variations in PPARG can be associated with susceptibility to glioma type 1 (GLM1) [MIM:[~~http~~://omim.org/entry/137800 137800]]. Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas. Note=Polymorphic PPARG alleles have been found to be significantly over-represented among a cohort of American patients with sporadic glioblastoma multiforme suggesting a possible contribution to disease susceptibility.	+	[[https://www.uniprot.org/uniprot/PPARG_HUMAN PPARG_HUMAN]] Note=Defects in PPARG can lead to type 2 insulin-resistant diabetes and hyptertension. PPARG mutations may be associated with colon cancer. Defects in PPARG may be associated with susceptibility to obesity (OBESITY) [MIM:[https://omim.org/entry/601665 601665]]. It is a condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat.<ref>PMID:9753710</ref> Defects in PPARG are the cause of familial partial lipodystrophy type 3 (FPLD3) [MIM:[https://omim.org/entry/604367 604367]]. Familial partial lipodystrophies (FPLD) are a heterogeneous group of genetic disorders characterized by marked loss of subcutaneous (sc) fat from the extremities. Affected individuals show an increased preponderance of insulin resistance, diabetes mellitus and dyslipidemia.<ref>PMID:12453919</ref> <ref>PMID:11788685</ref> Genetic variations in PPARG can be associated with susceptibility to glioma type 1 (GLM1) [MIM:[https://omim.org/entry/137800 137800]]. Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas. Note=Polymorphic PPARG alleles have been found to be significantly over-represented among a cohort of American patients with sporadic glioblastoma multiforme suggesting a possible contribution to disease susceptibility.
	== Function ==		== Function ==
-	[[~~http~~://www.uniprot.org/uniprot/PPARG_HUMAN PPARG_HUMAN]] Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the receptor binds to a promoter element in the gene for acyl-CoA oxidase and activates its transcription. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses.<ref>PMID:9065481</ref> <ref>PMID:16150867</ref> <ref>PMID:20829347</ref>	+	[[https://www.uniprot.org/uniprot/PPARG_HUMAN PPARG_HUMAN]] Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the receptor binds to a promoter element in the gene for acyl-CoA oxidase and activates its transcription. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses.<ref>PMID:9065481</ref> <ref>PMID:16150867</ref> <ref>PMID:20829347</ref>
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-dependent transcription factors that control various functions in human organism, including the control of glucose and lipid metabolism. PPARgamma is a target of TZD agonists, clinically used to improve insulin sensitivity whereas fibrates, PPARalpha ligands, lower serum triglyceride levels. We report here the structural studies of GL479, a synthetic dual PPARalpha/gamma agonist, designed by a combination of clofibric acid skeleton and a phenyldiazenyl moiety, as bioisosteric replacement of stilbene group, in complex with both PPARalpha and PPARgamma receptors. GL479 was previously reported as a partial agonist of PPARgamma and a full agonist of PPARalpha with high affinity for both PPARs. Our structural studies reveal different binding modes of GL479 to PPARalpha and PPARgamma, which may explain the distinct activation behaviors observed for each receptor. In both cases the ligand interacts with a Tyr located at helix 12 (H12), resulting in the receptor active conformation. In the complex with PPARalpha, GL479 occupies the same region of the ligand-binding pocket (LBP) observed for other full agonists, whereas GL479 bound to PPARgamma displays a new binding mode. Our results indicate a novel region of PPARs LBP that may be explored for the design of partial agonists as well dual PPARalpha/gamma agonists that combine, simultaneously, the therapeutic effects of the treatment of insulin resistance and dyslipidemia.	+
-		+
-	Different binding and recognition modes of GL479, a dual agonist of Peroxisome Proliferator-Activated Receptor alpha/gamma.,Dos Santos JC, Bernardes A, Giampietro L, Ammazzalorso A, De Filippis B, Amoroso R, Polikarpov I J Struct Biol. 2015 Jul 14. pii: S1047-8477(15)30031-9. doi:, 10.1016/j.jsb.2015.07.006. PMID:26185032<ref>PMID:26185032</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 4ci5" style="background-color:#fffaf0;"></div~~>	+

	==See Also==		==See Also==
Line 28:		Line 18:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Bernardes, A]]	+	[[Category: Bernardes A]]
-	[[Category: Polikarpov, I]]	+	[[Category: Polikarpov I]]
-	[[Category: Santos~~, J C]]~~	+	[[Category: Santos JC]]
-	~~[[Category: Dual agonist]]~~	+
-	~~[[Category: Nuclear protein]]~~	+
-	~~[[Category: Nuclear receptor~~]]	+

OCA at 09:04, 21 October 2020

OCA — Wed, 21 Oct 2020 09:04:55 GMT

←Older revision		Revision as of 09:04, 21 October 2020
Line 1:		Line 1:

	==Structural basis for GL479 a dual Peroxisome Proliferator-Activated Receptor gamma agonist==		==Structural basis for GL479 a dual Peroxisome Proliferator-Activated Receptor gamma agonist==
-	<StructureSection load='4ci5' size='340' side='right' caption='[[4ci5]], [[Resolution\|resolution]] 1.77Å' scene=''>	+	<StructureSection load='4ci5' size='340' side='right'caption='[[4ci5]], [[Resolution\|resolution]] 1.77Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4ci5]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CI5 OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4CI5 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4ci5]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CI5 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=4CI5 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=Y1N:2-METHYL-2-[4-[2-[4-[(E)-PHENYLDIAZENYL]PHENOXY]ETHYL]PHENOXY]PROPANOIC+ACID'>Y1N</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=Y1N:2-METHYL-2-[4-[2-[4-[(E)-PHENYLDIAZENYL]PHENOXY]ETHYL]PHENOXY]PROPANOIC+ACID'>Y1N</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4ci4\|4ci4]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4ci4\|4ci4]]</td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4ci5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ci5 OCA], [http://pdbe.org/4ci5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ci5 RCSB], [http://www.ebi.ac.uk/pdbsum/4ci5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ci5 ProSAT]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=4ci5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ci5 OCA], [http://pdbe.org/4ci5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ci5 RCSB], [http://www.ebi.ac.uk/pdbsum/4ci5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ci5 ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 23:		Line 23:

	==See Also==		==See Also==
-	*[[Peroxisome ~~Proliferator~~-~~Activated Receptors~~\|Peroxisome ~~Proliferator~~-~~Activated Receptors~~]]	+	*[[Peroxisome proliferator-activated receptor 3D structures\|Peroxisome proliferator-activated receptor 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
Line 29:		Line 29:
	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Bernardes, A]]		[[Category: Bernardes, A]]
	[[Category: Polikarpov, I]]		[[Category: Polikarpov, I]]

OCA at 12:19, 16 January 2019

OCA — Wed, 16 Jan 2019 12:19:11 GMT

←Older revision		Revision as of 12:19, 16 January 2019
Line 1:		Line 1:
		+
	==Structural basis for GL479 a dual Peroxisome Proliferator-Activated Receptor gamma agonist==		==Structural basis for GL479 a dual Peroxisome Proliferator-Activated Receptor gamma agonist==
	<StructureSection load='4ci5' size='340' side='right' caption='[[4ci5]], [[Resolution\|resolution]] 1.77Å' scene=''>		<StructureSection load='4ci5' size='340' side='right' caption='[[4ci5]], [[Resolution\|resolution]] 1.77Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4ci5]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CI5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CI5 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4ci5]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CI5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CI5 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=Y1N:2-METHYL-2-[4-[2-[4-[(E)-PHENYLDIAZENYL]PHENOXY]ETHYL]PHENOXY]PROPANOIC+ACID'>Y1N</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=Y1N:2-METHYL-2-[4-[2-[4-[(E)-PHENYLDIAZENYL]PHENOXY]ETHYL]PHENOXY]PROPANOIC+ACID'>Y1N</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4ci4\|4ci4]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4ci4\|4ci4]]</td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ci5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ci5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ci5 RCSB], [http://www.ebi.ac.uk/pdbsum/4ci5 PDBsum]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ci5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ci5 OCA], [http://pdbe.org/4ci5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ci5 RCSB], [http://www.ebi.ac.uk/pdbsum/4ci5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ci5 ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 19:		Line 20:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 4ci5" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Peroxisome Proliferator-Activated Receptors\|Peroxisome Proliferator-Activated Receptors]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Bernardes, A]]		[[Category: Bernardes, A]]
	[[Category: Polikarpov, I]]		[[Category: Polikarpov, I]]

OCA at 13:46, 5 August 2015

OCA — Wed, 05 Aug 2015 13:46:22 GMT

←Older revision		Revision as of 13:46, 5 August 2015
Line 11:		Line 11:
	== Function ==		== Function ==
	[[http://www.uniprot.org/uniprot/PPARG_HUMAN PPARG_HUMAN]] Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the receptor binds to a promoter element in the gene for acyl-CoA oxidase and activates its transcription. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses.<ref>PMID:9065481</ref> <ref>PMID:16150867</ref> <ref>PMID:20829347</ref>		[[http://www.uniprot.org/uniprot/PPARG_HUMAN PPARG_HUMAN]] Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the receptor binds to a promoter element in the gene for acyl-CoA oxidase and activates its transcription. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses.<ref>PMID:9065481</ref> <ref>PMID:16150867</ref> <ref>PMID:20829347</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-dependent transcription factors that control various functions in human organism, including the control of glucose and lipid metabolism. PPARgamma is a target of TZD agonists, clinically used to improve insulin sensitivity whereas fibrates, PPARalpha ligands, lower serum triglyceride levels. We report here the structural studies of GL479, a synthetic dual PPARalpha/gamma agonist, designed by a combination of clofibric acid skeleton and a phenyldiazenyl moiety, as bioisosteric replacement of stilbene group, in complex with both PPARalpha and PPARgamma receptors. GL479 was previously reported as a partial agonist of PPARgamma and a full agonist of PPARalpha with high affinity for both PPARs. Our structural studies reveal different binding modes of GL479 to PPARalpha and PPARgamma, which may explain the distinct activation behaviors observed for each receptor. In both cases the ligand interacts with a Tyr located at helix 12 (H12), resulting in the receptor active conformation. In the complex with PPARalpha, GL479 occupies the same region of the ligand-binding pocket (LBP) observed for other full agonists, whereas GL479 bound to PPARgamma displays a new binding mode. Our results indicate a novel region of PPARs LBP that may be explored for the design of partial agonists as well dual PPARalpha/gamma agonists that combine, simultaneously, the therapeutic effects of the treatment of insulin resistance and dyslipidemia.
		+
		+	Different binding and recognition modes of GL479, a dual agonist of Peroxisome Proliferator-Activated Receptor alpha/gamma.,Dos Santos JC, Bernardes A, Giampietro L, Ammazzalorso A, De Filippis B, Amoroso R, Polikarpov I J Struct Biol. 2015 Jul 14. pii: S1047-8477(15)30031-9. doi:, 10.1016/j.jsb.2015.07.006. PMID:26185032<ref>PMID:26185032</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
	== References ==		== References ==
	<references/>		<references/>

OCA at 11:04, 24 December 2014

OCA — Wed, 24 Dec 2014 11:04:03 GMT

←Older revision		Revision as of 11:04, 24 December 2014
Line 1:		Line 1:
-	'''~~Unreleased structure~~'''	+	==Structural basis for GL479 a dual Peroxisome Proliferator-Activated Receptor gamma agonist==
-		+	<StructureSection load='4ci5' size='340' side='right' caption='[[4ci5]], [[Resolution\|resolution]] 1.77Å' scene=''>
-	~~The entry~~ 4ci5 is ~~ON HOLD until Paper Publication~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[4ci5]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CI5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CI5 FirstGlance]. <br>
-	~~Authors~~: ~~SANTOS~~, J.C., ~~BERNARDES~~, A., ~~POLIKARPOV~~, I.	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=Y1N:2-METHYL-2-[4-[2-[4-[(E)-PHENYLDIAZENYL]PHENOXY]ETHYL]PHENOXY]PROPANOIC+ACID'>Y1N</scene></td></tr>
-		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4ci4\|4ci4]]</td></tr>
-	~~Description~~: ~~Structural basis~~ for ~~GL479~~ a ~~dual Peroxisome Proliferator~~-~~Activated Receptor gamma~~ agonist	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ci5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ci5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ci5 RCSB], [http://www.ebi.ac.uk/pdbsum/4ci5 PDBsum]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/PPARG_HUMAN PPARG_HUMAN]] Note=Defects in PPARG can lead to type 2 insulin-resistant diabetes and hyptertension. PPARG mutations may be associated with colon cancer. Defects in PPARG may be associated with susceptibility to obesity (OBESITY) [MIM:[http://omim.org/entry/601665 601665]]. It is a condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat.<ref>PMID:9753710</ref> Defects in PPARG are the cause of familial partial lipodystrophy type 3 (FPLD3) [MIM:[http://omim.org/entry/604367 604367]]. Familial partial lipodystrophies (FPLD) are a heterogeneous group of genetic disorders characterized by marked loss of subcutaneous (sc) fat from the extremities. Affected individuals show an increased preponderance of insulin resistance, diabetes mellitus and dyslipidemia.<ref>PMID:12453919</ref> <ref>PMID:11788685</ref> Genetic variations in PPARG can be associated with susceptibility to glioma type 1 (GLM1) [MIM:[http://omim.org/entry/137800 137800]]. Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas. Note=Polymorphic PPARG alleles have been found to be significantly over-represented among a cohort of American patients with sporadic glioblastoma multiforme suggesting a possible contribution to disease susceptibility.
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/PPARG_HUMAN PPARG_HUMAN]] Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the receptor binds to a promoter element in the gene for acyl-CoA oxidase and activates its transcription. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses.<ref>PMID:9065481</ref> <ref>PMID:16150867</ref> <ref>PMID:20829347</ref>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Bernardes, A]]
		+	[[Category: Polikarpov, I]]
		+	[[Category: Santos, J C]]
		+	[[Category: Dual agonist]]
		+	[[Category: Nuclear protein]]
		+	[[Category: Nuclear receptor]]

OCA at 08:50, 18 December 2013

OCA — Wed, 18 Dec 2013 08:50:25 GMT

←Older revision		Revision as of 08:50, 18 December 2013
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 4ci5 is ON HOLD until ~~sometime in the future~~	+	The entry 4ci5 is ON HOLD until Paper Publication

	Authors: SANTOS, J.C., BERNARDES, A., POLIKARPOV, I.		Authors: SANTOS, J.C., BERNARDES, A., POLIKARPOV, I.

	Description: Structural basis for GL479 a dual Peroxisome Proliferator-Activated Receptor gamma agonist		Description: Structural basis for GL479 a dual Peroxisome Proliferator-Activated Receptor gamma agonist

OCA: Protected "4ci5" [edit=sysop:move=sysop]

OCA — Wed, 11 Dec 2013 12:48:20 GMT

Protected "4ci5" [edit=sysop:move=sysop]

←Older revision

Revision as of 12:48, 11 December 2013

OCA: New page: '''Unreleased structure''' The entry 4ci5 is ON HOLD until sometime in the future Authors: SANTOS, J.C., BERNARDES, A., POLIKARPOV, I. Description: Structural basis for GL479 a dual Pe...

OCA — Wed, 11 Dec 2013 12:48:19 GMT

New page: '''Unreleased structure''' The entry 4ci5 is ON HOLD until sometime in the future Authors: SANTOS, J.C., BERNARDES, A., POLIKARPOV, I. Description: Structural basis for GL479 a dual Pe...

New page

'''Unreleased structure'''

The entry 4ci5 is ON HOLD until sometime in the future

Authors: SANTOS, J.C., BERNARDES, A., POLIKARPOV, I.

Description: Structural basis for GL479 a dual Peroxisome Proliferator-Activated Receptor gamma agonist